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Response to psychedelic drugs may depend on small genetic differences

In vitro study reports that natural mutations that change a serotonin receptor’s structure may impact drugs’ potency

by Attabey Rodríguez Benítez, special to C&EN
August 19, 2022

Psychiatrists are interested in using psychedelic compounds as an alternative therapy for mental disorders like depression and post-traumatic stress disorder. In clinical trials, some participants report mental health improvements after treatment with psychedelic substances, yet others report no significant effect. A team at the University of North Carolina at Chapel Hill has now reported that natural variations in a serotonin receptor could affect how some psychedelic compounds interact with people’s cells, which could be related to whether patients respond to treatments (ACS Chem. Neurosci. 2022, DOI: 10.1021/acschemneuro.1c00815).

Line structures of psilocin, mescaline, LSD, and 5-MeO-DMT, or 5-methoxy-N,N-dimethyltryptamine.
Researchers measured how strongly these four psychoactive molecules bound to natural variations of a human serotonin receptor.

The team synthesized seven naturally occurring human variants of the 5-HT2A serotonin receptor, a protein made in neurons that binds to a precursor of serotonin called 5-hydroxytryptamine. Upon binding, the receptor becomes activated, triggering changes in emotion and cognition. However, other molecules, including psychedelic drugs, can activate this receptor too.

To observe drug responses, the researchers gauged the potency of psychedelic compounds including psilocin, LSD, mescaline, and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) in vitro by measuring the concentration needed to bind the compounds to 50% of each of the receptor variants, also known as EC50. They observed that psilocin bound to the non-mutated form of the receptor with a potency seven times as high as it bound to some of the variants. On the flip side, when binding to mescaline, some receptor variants showed a potency nine times as high as the non-mutated variant.

“It may not seem like a huge shift in potency in a field where things can be many orders of magnitude different,” says Sam Slocum, one of the authors of the study. “But in these kinds of treatments, every detail matters when determining what level of brain exposure you need.”

Because these genetic variations impact how the receptor interacts with various psychedelics, sequencing trial participants’ DNA might be helpful when evaluating their treatment response, Slocum says.



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